Noninvasive ventilation allows gastrostomy tube placement in patients with advanced ALS.

The use of noninvasive positive pressure ventilation for ventilatory support during percutaneous endoscopic gastrostomy (PEG) tube placement is described in five patients with advanced ALS, four having significant bulbar symptoms. No respiratory complications occurred in any of these patients, who were considered to be at high risk for PEG placement because of severe ventilatory impairment and might not otherwise have been considered for this procedure.

Economic aspects of lung volume reduction surgery.

OBJECTIVE: To investigate the economics of lung volume reduction surgery. DESIGN: Medical center and physician charges obtained from billing records. SETTING: Academic health center. PATIENTS: Twenty-three consecutive patients undergoing lung volume reduction surgery at a single institution who were discharged from the hospital prior to November 1, 1995. OUTCOME MEASURES: Length of hospital stay, mortality, medical center charges and professional fees, and sponsor reimbursement. RESULTS: Median hospital stay was 8.0 days and there were no deaths. The median charge was $26,669 (range, $20,032 to $75,561) of which 73% was for medical center services and 27% was for physician services. Fees for medical center rooms and operating suite time accounted for 71% of medical center charges. Charges by surgeons and anesthesiologists accounted for 77% of professional fees. Total charges were directly related to length of stay (r2 = 0.95). Median reimbursement for medical center services was $22,264 (114%; range, $13,333 to $123,362) and for physician services was $2,783 (34%; range, $2,597 to $11,265), resulting in a median total reimbursement that represented 94% of total charges. The median reimbursement-to-cost ratio was 1.22, compared with 1.05 for all medical services in fiscal year 1995. CONCLUSIONS: These data must now be assessed relative to outcomes such as quality of life, patient function, and long-term survival to determine cost-effectiveness of lung volume reduction surgery.

Clinical experimentation. Lessons from lung volume reduction surgery.

Although the advancement of medical science can occur only with the systematic evaluation of new interventions, novel therapies continue to be introduced and accepted prior to thorough study. The recent development of lung volume reduction surgery for emphysema provides an illustration of the unwillingness or the inability of the medical community, unconstrained by legal or reimbursement limitations, to assure the safety and efficacy of a new procedure prior to widespread utilization. Medical practitioners must learn to recognize the experimental nature of new procedures independent of the courts and third-party payers. The nature of the informed consent that must be obtained for an experimental therapy is different from that which is required for standard medical practice and this difference can provide a test of whether a new treatment is experimental. A comparison between the introduction of lung volume reduction surgery and the rigorous scrutiny required of any pharmacologic interventions for emphysema underscores the double standard that exists for evaluating new surgical (and some medical) innovations. Such a double standard cannot be defended on ethical or scientific grounds. Specific changes in the way experimental therapies are introduced and disseminated are suggested. Until all new medical and surgical interventions are required to undergo a thorough evaluation prior to becoming standard of case, the promise of evidence-based medicine can never be fulfilled.

Intrathoracic lymphadenopathy. A rare manifestation of rheumatoid pulmonary disease.

This is the first antemortem report of a patient with long-standing RA and interstitial lung disease who developed reactive mediastinal adenopathy coincident with increases in the activity of his interstitial process. Mediastinal adenopathy was discovered by means of CT of the chest as part of an evaluation of interstitial lung disease. The increasing use of better imaging techniques for this purpose will undoubtedly reveal more patients with this finding. Mediastinal lymphadenopathy complicating rheumatoid lung is clinically relevant; speculation is provided regarding the mechanism of the lymph node enlargement in this setting.

Underestimation of mortality following lung volume reduction surgery resulting from incomplete follow-up.

STUDY OBJECTIVES: Incomplete follow-up can bias interpretation of data that are collected in longitudinal studies. We noted that many patients failed to return for follow-up in a study of effect of lung volume reduction surgery (LVRS) on quality of life (QOL). Accordingly, we designed this investigation to determine the reasons patients dropped out, and to assess differences between those who continued in the study (attendees) and those who did not (nonattendees). DESIGN: Telephone survey. SUBJECTS: Patients with advanced emphysema who had undergone LVRS and had previously agreed to participate in a longitudinal QOL study. RESULTS: No differences were found with regard to age, gender, preoperative pulmonary function, or oxygen use between attendees and nonattendees. Long-term mortality in nonattendees (27%) was considerably greater than that seen in attendees (3%, p < 0.05). Distance from the hospital, financial burden, and living out of the region were the most common reasons cited by surviving nonattendees for their failure to return for follow-up. CONCLUSIONS: Studies reporting the long-term mortality after LVRS can be biased in the direction of underestimating the true value if they are compromised by incomplete follow-up.

Diaphragm thickening during inspiration.

Ultrasound has been used to measure diaphragm thickness (Tdi) in the area where the diaphragm abuts the rib cage (zone of apposition). However, the degree of diaphragm thickening during inspiration reported as obtained by one-dimensional M-mode ultrasound was greater than that predicted by using other radiographic techniques. Because two-dimensional (2-D) ultrasound provides greater anatomic definition of the diaphragm and neighboring structures, we used this technique to reevaluate the relationship between lung volume and Tdi. We first established the accuracy and reproducibility of 2-D ultrasound by measuring Tdi with a 7.5-MHz transducer in 26 cadavers. We found that Tdi measured by ultrasound correlated significantly with that measured by ruler (R2 = 0.89), with the slope of this relationship approximating a line of identity (y = 0.89x + 0.04 mm). The relationship between lung volume and Tdi was then studied in nine subjects by obtaining diaphragm images at the five target lung volumes [25% increments from residual volume (RV) to total lung capacity (TLC)]. Plots of Tdi vs. lung volume demonstrated that the diaphragm thickened as lung volume increased, with a more rapid rate of thickening at the higher lung volumes [Tdi = 1.74 vital capacity (VC)2 + 0.26 VC + 2.7 mm] (R2 = 0. 99; P < 0.001) where lung volume is expressed as a fraction of VC. The mean increase in Tdi between RV and TLC for the group was 54% (range 42-78%). We conclude that 2-D ultrasound can accurately measure Tdi and that the average thickening of the diaphragm when a subject is inhaling from RV to TLC using this technique is in the range of what would be predicted from a 35% shortening of the diaphragm.

Surgical options for patients with advanced emphysema.

Since the early 1900s, a variety of operations have been suggested for emphysema but, with the exception of giant bullectomy, an option in only a small fraction of patients, none has proven effective. Data collected by a number of academic medical centers indicate that LVRS may ameliorate symptoms and improve pulmonary physiology, function, and quality of life in appropriately selected patients with emphysema. Accordingly, LVRS may provide an opportunity to intervene in a rapid, effective, and, possibly, cost-effective manner in a debilitating, chronic disease. That is an extraordinarily attractive proposition for both patients and physicians alike. But a number of questions remain: (1) What is the effect of LVRS compared with maximal medical therapy? (2) What is the duration of any beneficial effect of LVRS? (3) What is the best operative approach? (4) What patient characteristics predict good and bad outcomes? (5) What is the role of pre- and, possibly, postoperative pulmonary rehabilitation? (6) Does LVRS adversely affect the rate of loss of lung function over time, as some have suggested? (7) What is the cost of LVRS compared with standard medical therapy? (8) Can the procedure be performed safely in nontransplant centers? (9) What is the effect on disease-specific quality of life? (10) Does it affect mortality? A prospective, randomized controlled trial involving 18 selected centers will begin in the fall of 1997 under the sponsorship of the Health Care Financing Corporation (the administrators of Medicare) and the National Institutes of Health. We strongly support the creative, collaborative approach that has been taken by those two government agencies to stimulate this study. The need for controlled trials of new therapies cannot be overstated; only with such trials can the questions enumerated above be answered with certainty.

Evaluation and management of patients with pulmonary disease before thoracic and cardiovascular surgery.

The risks of respiratory complications after thoracic and cardiovascular surgeries are particularly high for patients with chronic pulmonary disease and are associated with prolonged hospital stays and increased mortality. The primary goals of preoperative management are to identify risk factors and institute interventions likely to reduce subsequent postoperative pulmonary complications. Smoking, symptomatic obstructive lung disease, respiratory infection, obesity, and malnutrition are all potentially modifiable risk factors. Chest physiotherapy is indicated in all patients regardless of risk factor profile. Providing a thoughtfully designed, multifaceted course of preoperative care can result in a clinically significant reduction in postoperative morbidity and mortality, particularly if instituted well in advance of surgery.

Adverse effects of low-flow oxygen therapy.

Exposure to oxygen at a high FIO2 can result in substantial damage to several organ systems. In contrast, low-flow oxygen is generally quite safe. Although there have been reports of lung tissue injury with low-flow oxygen, the benefits of this therapy in appropriately selected individuals clearly outweighs the small risks. Elevations in PaCO2 occur in some COPD patients receiving low-flow oxygen and appear to be related to changes in ventilation-perfusion matching in the lung and carbon dioxide transport in the blood stream rather than to reductions in respiratory drive as previously thought. The effect is generally small in magnitude and is not progressive in response to oxygen therapy alone. Nonmedical hazards such as frostbite and fire related to oxygen equipment have been described but are unusual. Minor problems such as skin rash or nasal irritation in those using low-flow oxygen are usually easily handled with topical treatments. Social and psychological problems, resulting from a perceived stigma of wearing oxygen may lead to social isolation of the patient and should be addressed with appropriate counseling and education.

Lung-volume reduction surgery for diffuse emphysema: radiologic assessment of changes in thoracic dimensions.

Patients with severe, diffuse emphysema may be candidates for pneumectomy (lung-volume reduction surgery, LVRS) to improve lung and respiratory muscle function. To identify candidates who might benefit from this surgery, it is necessary to understand how lung volumes and respiratory function are effected. In this article, the authors demonstrate a significant difference in lung size on chest radiographs obtained before and after surgery. Thirty-five of 71 consecutive patients undergoing LVRS had both preoperative and postoperative chest radiographs and pulmonary function tests available for retrospective review. Preoperative and postoperative measurements of lung height, transthoracic diameters, mediastinal width, heart size, diaphragmatic arc, and intercostal spaces were compared using paired t-tests. Radiographic measurements where also correlated with changes in lung volumes as measured by pulmonary function tests. Lung heights (right, left, mean lateral) and coronal diameter at the aortic arch were reduced after surgery (all p < 0.05). Forced vital capacity, forced expiratory volume in 1 second (FEV1), and vital capacity increased, and total lung capacity and residual volume decreased after surgery (all p < 0.05). Left lung height showed a significant correlation (p = 0.025) with FEV1; all other correlations between radiographic changes and pulmonary function test changes were not significant. The explanation for improved lung function in patients after LVRS is not completely clear and is probably multifactorial. Radiologic alterations reflect anatomic changes caused by surgery and support the theory that modifications of chest wall configuration occur and are likely responsible, in part, for improved symptomatology and respiratory function.

Management of pulmonary complications in neuromuscular disease.

The clinician working with patients with neuromuscular disease should be aware of the effects of muscle weakness on the respiratory system. Symptoms may present insidiously and can result in progressive loss of function, respiratory failure, and even death. A number of techniques, including several forms of mechanical ventilation as well as physical aids to assist airway hygiene, are available and are effective in improving symptoms and survival in appropriately selected patients with neuromuscular disease.

Restrictive pulmonary disease due to interlobular septal fibrosis associated with disseminated infection by Strongyloides stercoralis.

Strongyloidiasis is caused by the nematode Strongyloides stercoralis. The parasite has a unique life cycle that enables it to cause a hyperinfection syndrome in which pulmonary involvement is characteristic. We describe the case of a 68-yr-old Hispanic male from Puerto Rico with disseminated strongyloidiasis who developed intense granulomatous reaction in the lung associated with interlobular septal fibrosis. Granulomatous lung disease leading to fibrosis within the lung has been well demonstrated in schistosomiasis, another parasitic disease. This case represents the first report, as far as we are aware, of fibrosis within the lung and restrictive pulmonary disease in association with Strongyloides stercoralis.

Interaction of a nuclear location signal with isolated nuclear envelopes and identification of signal-binding proteins by photoaffinity labeling.

The nuclear envelope (NE) separates the two major compartments of eukaryotic cells, the nucleus and the cytoplasm. Recent studies suggest that the uptake of nuclear proteins into the nucleus is initiated by binding of nuclear location signals (NLSs) contained within these proteins to receptors in the NE, followed by translocation through the nuclear pore complex. To examine the binding step without interference from intranuclear events, we have used a system consisting of (i) purified rat liver NEs fixed onto glass slides and (ii) the prototype simian virus 40 large T antigen (SV40 T) NLS conjugated to nonnuclear carrier proteins, and we have visualized the receptor-ligand interaction by indirect immunofluorescence. In this system, incubation of isolated NEs with the wild-type SV40 T NLS conjugate with carrier proteins resulted in binding that was signal sequence-dependent, could be competitively blocked with excess conjugated and unconjugated wild-type peptide, did not require ATP, and was not affected by the transport-inhibiting lectin wheat germ agglutinin. In contrast, only minimal binding was observed with a mutant SV40 T NLS conjugate. These results are consistent with those obtained in other, more complex in vitro systems and suggest that binding of the SV40 T NLS is receptor-mediated. Binding is largely abolished by extraction of the NE with the nonionic detergent Triton X-100, suggesting that the receptor is soluble in detergent. We find in the Triton X-100 supernatant four major NLS-binding proteins with apparent molecular masses of 76, 67, 59, and 58 kDa by photoaffinity labeling with a highly specific crosslinker, azido-NLS. The reduced complexity of the system described here should be useful for the functional study of other potential NLSs for the identification and isolation of their binding sites and for the screening of antibodies raised against these binding sites.

Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery.

Patients with chronic obstructive pulmonary disease have abnormal breathing and ventilatory muscle recruitment patterns at rest and during exercise, and these alterations may contribute to the limited exercise capacity seen in this disease. Lung volume reduction surgery (LVRS), a recently described treatment for emphysema, is reported to improve exercise performance. We studied the breathing and ventilatory muscle recruitment (VMR) patterns in eight patients with severe chronic obstructive lung disease (median FEV1 = 0.79 L, range 0.46 to 1.13 L) by measuring esophageal and gastric pressure measurements as well as tidal volumes (VT), respiratory rates (f), inspiratory (TI) and expiratory (TE) times, and watts at rest and during maximal exercise, before and 3 mo after lung volume reduction surgery. Maximal exercise capacity increased a median of 49% (median increase 17 watts, range 6 to 44 watts, p < 0.05) and maximal minute ventilation (VEmax) increased by a median of 22% (median increase 6.5 L/min, range 3 to 25 L/min, p < 0.05). At isowatt exercise after surgery, VT increased 0.31 L (range 0.07 to 0.69 L) and f decreased four breaths/min (range +0.5 to -15 breaths/min). Dyspnea scores as measured by a visual analog scale (VAS) decreased significantly at rest and at peak exercise after surgery. End-expiratory esophageal (Pes) and gastric (Pga) pressures at rest and at isowatt exercise decreased. A rightward shift in the slope of the Pes versus Pga plot was also observed suggesting increased use of the diaphragm after surgery. Our data indicate that LVRS improves the mechanics of breathing both at rest and during exercise.

Lung volume reduction surgery has variable effects on blood gases in patients with emphysema.

Most studies of bilateral lung volume reduction surgery (LVRS) report increases in arterial oxygenation (PaO2). Some suggest this results from an increased alveolar ventilation, but others imply that ventilation-perfusion heterogeneity is reduced. We measured arterial blood gases (ABGs) on air before and 3 mo following LVRS in 46 patients (61% of eligible patients), estimate the difference between alveolar and arterial O2 (AaPO2), and correlated the changes observed with preoperative ABGs, and with pre-and postoperative pulmonary function. The mean +/- SD change in PaO2 and AaPO2 was +3 +/- 10 mm Hg (p = 0.058) and +1 +/- 11 mm Hg (p = NS), respectively, and the range of change was large (-17 to +29 mm Hg and -24 to +23 mm Hg, respectively). The mean change in PaCO2 was -3 +/- 5 mm Hg (p < 0.05) and ranged from -11 to +5 mm Hg. Changes in PaO2 and AaPO2 were poorly correlated with changes in PaCO2 or with pre- or postoperative pulmonary function. Although some patients had a marked improvement in ABGs following LVRS, almost as many deteriorated. On average, only minimal effects were seen. Although mean alveolar ventilation improved somewhat, the effect of LVRS on PaO2 primarily resulted from alterations in ventilation-perfusion heterogeneity.

Lung volume reduction surgery improves maximal O2 consumption, maximal minute ventilation, O2 pulse, and dead space-to-tidal volume ratio during leg cycle ergometry.

Early experience suggests that lung volume reduction surgery improves exercise tolerance as measured by the 6-min walk distance in patients with emphysema. To identify the physiologic mechanism(s) by which lung volume reduction surgery improved exercise, we performed progressive cardiopulmonary exercise testing, including rest and peak exercise blood gas determinations, on 21 consecutive patients before and 3 mo after lung volume reduction surgery. Maximal work (median, range, % change) increased 17.5 watts (-13 to +44 watts, 46%, p < 0.05), maximal oxygen consumption increased 0.16 L/min (-0.17 to +0.48, 25%, p < 0.05), maximal ventilation increased 6.6 L/min (-7 to +26 L/min, 27%, p < 0.05), and the dead space/tidal volume ratio at peak exercise decreased 0.07 (-0.22 to +0.09, 12%, p < 0.05), exclusively as a result of an increase in the tidal volume. After lung volume reduction surgery heart rate decreased at the point of isowatt exercise, from 115 to 111 beats/min (p < 0.05). No difference was observed in the other physiologic variables measured at isowatt exercise. In 13 patients exercised while breathing room air, the alveolar-to-arterial O2 difference increased, and the arterial O2 tension decreased from rest to peak exercise both before and after the operation, but significant changes in this response were not observed after surgery. The primary problem limiting exercise performance in these patients was the limited ventilatory capacity as 16 and 13 of the 21 subjects developed acute respiratory acidemia at peak exercise before and after surgery, respectively. Lung volume reduction surgery in patients with severe emphysema improved maximal ventilation, thereby improving maximal exercise performance.

GTP-binding proteins in rat liver nuclear envelopes.

Nuclear transport as well as reassembly of the nuclear envelope (NE) after completion of mitosis are processes that have been shown to require GTP and ATP. To study the presence and localization of GTP-binding proteins in the NE, we have combined complementary techniques of [alpha-32P]GTP binding to Western-blotted proteins and UV crosslinking of [alpha-32P]GTP with well-established procedures for NE subfractionation. GTP binding to blotted NE proteins revealed five low molecular mass GTP-binding proteins of 26, 25, 24.5, 24, and 23 kDa, and [alpha-32P]GTP photoaffinity labeling revealed major proteins with apparent molecular masses of 140, 53, 47, 33, and 31 kDa. All GTP-binding proteins appear to localize preferentially to the inner nuclear membrane, possibly to the interface between inner nuclear membrane and lamina. Despite the evolutionary conservation between the NE and the rough endoplasmic reticulum, the GTP-binding proteins identified differed between these two compartments. Most notably, the 68- and 30-kDa GTP-binding subunits of the signal recognition particle receptor, which photolabeled with [alpha-32P]GTP in the rough endoplasmic reticulum fraction, were totally excluded from the NE fraction. Conversely, a major 53-kDa photolabeled protein in the NE was absent from rough endoplasmic reticulum. Whereas Western-blotted NE proteins bound GTP specifically, all [alpha-32P]GTP photolabeled proteins could be blocked by competition with ATP, although with a competition profile that differed from that obtained with GTP. In comparative crosslinking studies with [alpha-32P]ATP, we have identified three specific ATP-binding proteins with molecular masses of 160, 78, and 74 kDa. The localization of GTP- and ATP-binding proteins within the NE appears appropriate for their involvement in nuclear transport and in the GTP-dependent fusion of nuclear membrane vesicles required for reassembly of the nucleus after mitosis.